
Sitagliptin dihydrogen phosphate (02), chemically named as (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine dihydrogen phosphate, is an oral antihyperglycemic of the dipeptidyl peptidase-IV (DPP-IV) inhibitor class. Inhibition of DPP-IV, an enzyme that inactivates both glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), represents a recent approach to the treatment and prevention of type-2 diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM). Sitagliptin also has an effect on appetite as it slows down gastric motility and induces a feeling of satiety. This reduction of appetite can help patients to lose weight which is also a useful effect in patients with diabetes.
Several processes have been disclosed in the prior art for the preparation of sitagliptin and its analogues. The process disclosed in patent U.S. Pat. No. 6,699,871, outlined in Scheme 1, involves the preparation of the intermediates (3R)-3-[N-(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (07) and 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (11) followed by their coupling to afford Boc-protected sitagliptin base (12), which was deprotected using methanolic hydrochloride to obtain sitagliptin hydrochloride (13).
However, the process disclosed in patent U.S. Pat. No. 6,699,871 suffers from the major disadvantage that the purification and synthesis of intermediates (07) and (12) require the use of preparative chiral HPLC and preparative HPLC respectively, which are very expensive and inconvenient techniques on an industrial scale. In addition, the process involves the use of the toxic and harmful reagent diazomethane.
In another prior art process, disclosed in patent application WO 2004/085661, sitagliptin free base (01) was synthesized by the process illustrated in Scheme 2, which involves synthesis of keto-amide (14) from Meldrum's adduct (19) and 3-trifluoromethyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (11). The intermediate (14) was further treated with (S)-phenylglycine amide in isopropanol and acetic acid to obtain amide (15), which was further converted into the amide (16) by asymmetric hydrogenation at 90 psi and 22° C. for 24 hours in the presence of PtO2 as catalyst. The intermediate (16) was converted into sitagliptin free base (01) by a debenzylation reaction carried out at 40 psi at 50° C. in the presence of 20% palladium hydroxide on carbon.
However, the processes disclosed in patent application WO 2004/085661 are not suitable for industrial production as they involve expensive agents like PtO2 and palladium hydroxide and require reaction at high pressure for more than 24 hours.
In another prior art process, disclosed in patent application US 2006/194977, sitagliptin dihydrogen phosphate salt (02) was prepared by the process outlined in Scheme 3. Intermediate (14), prepared by reaction of Meldrum's adduct (19) and 3-trifluoromethyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (11), was further converted into enamine (20) by use of ammonium acetate in methanol. The enamine (20) was further converted into enantiomerically enriched sitagliptin free base (01) by asymmetric reduction using Josiphos catalyst and chloro(1,5-cyclooctadiene) rhodium (I) dimer. The asymmetric synthesis involves hydrogenation of the enamine (20) at 200 psi at 50° C. for 13 hours to obtain enantiomerically enriched sitagliptin free base (01).
However, this process is not suitable for industrial production as it involves a very expensive chiral catalyst and requires reaction at high pressure for more than 10 hours.
A further process for the synthesis of sitagliptin free base (01) is disclosed in patent application WO 2004/087650. The process, outlined in Scheme 4, involves the synthesis of methyl 4-(2,4,5-trifluorophenyl)acetoacetate (21) by refluxing Meldrum's adduct (19) in methanol. The β-ketoester (21) formed was further subjected to asymmetric hydrogenation using ruthenium dichloride and (S)-BINAP to obtain (3S)-4-(2,4,5,-trifluorophenyl)-3-hydroxybutanoic acid (23), which was further converted into the oxazetidine (25) via hydroxy intermediate (24). The oxazetidine (25) was converted into (3R)-3-[(benzyloxy)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (26) and this was further converted into enantiomerically enriched sitagliptin free base (01) and sitagliptin dihydrogen phosphate (02).
However, the processes disclosed in patent application WO 2004/087650 are not suitable for industrial production as they involve a very expensive chiral catalyst and require reaction at high pressure.
As discussed above, the prior art teaches a variety of asymmetric syntheses to prepare enantiomerically enriched β-amino acids and their derivatives in the preparation of sitagliptin. The prior art also illustrates the importance of β-amino acid derivatives, in particular β-amino esters and amides, as key intermediates for the synthesis of sitagliptin free base (01) and sitagliptin dihydrogen phosphate (02). However, as discussed, the prior art processes suffer from various disadvantages with respect to commercial production.
In view of the importance of sitagliptin free base (01) and its dihydrogen phosphate salt (02) for anti-diabetic treatment, there is a great need for a simple, convenient, inexpensive and commercially viable process for the synthesis of sitagliptin with a commercially acceptable yield and purity.
Optical resolution is a particularly convenient technique for the commercial production of chiral molecules as the technique eliminates the problems associated with asymmetric synthesis. Surprisingly, the resolution of racemic β-amino acids or derivatives to obtain enantiomerically enriched β-amino acids or derivatives and their subsequent conversion into enantiomerically enriched sitagliptin free base (01) and its dihydrogen phosphate salt (02) has not been reported in any of the prior art.
Surprisingly, the present inventors have developed a method of resolution of racemic β-amino acid derivatives, in particular β-amino esters, to obtain enantiomerically enriched β-amino acid derivatives which are extremely suitable for the synthesis of enantiomerically pure sitagliptin and salts thereof.